The goal of the proposed research is to investigate the mechanisms through which increased airflow alters the collateral system resistance (Rcs) in the canine lung periphery. The central hypothesis is that the collateral system response to increased airflow is a direct function of evaporative water loss. The underlying mechanism may involve either airway cooling or airway drying (i.e., changes in the osmotic environment of the pulmonary mucosa). These changes could trigger a cascade of events that lead to a number of alternative pathways that affect Rcs. Each pathway could act simultaneously and synergistically to stimulate mediator release, trigger muscarinic or adrenergic activity, or directly affect airway smooth muscle and epithelium. Experiments are described in which an animal model is used to examine various mechanisms that may be involved in exercise, cold air, and hyperventilation induced bronchospasm. The specific objectives of this research are to: 1) Define the stimulus responsible for airflow induced bronchospasm (AIB); 2) Determine the effect of AIB on peripheral airway reactivity; 3) Administer pharmacologic agents that modify the response of the collateral system to challenge with dry air; 4) Determine the role of pulmonary and bronchial circulations in AIB; 5) Examine in vivo/in vitro correlations of AIB; and 6) Characterize delayed or late responses to dry air challenge. Experiments will utilize 1) the wedged bronchoscope technique to monitor Rcs, deliver aerosols, and challenge the lung periphery with increased rates of airflow; 2) specially designed thermisters and probes to monitor airway wall temperature (Taw) and the osmolarity of airway fluids, respectively; 3) bronchoalveolar lavage to examine the effect of high flow on cell profiles and mediator release; and 4) various pharmacologic and nonpharmocologic agents in an attempt to alter in vivo responses to increased airflow, and alter in vitro responses of smooth muscle and parenchyma following a variety of challenges. The response of the peripheral lung to increased airflow is of particular interest considering the fact that many asthmatics exhibit small airways obstruction following a period of exercise. The results of this study should provide a more complete understanding of the underlying mechanisms responsible for airflow-induced responses of the airways.
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